Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann et al, Ann. N.Y. Acad. Sci. 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 960704).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al, Fertility and Sterility 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann. N.Y. Acad. Sci. 761,224, 1995).
Jones et al (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A. 
Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones et al described compound C U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998). 
Zhi et al described the ether G as a PR antagonist (J. Med. Chem. 41, 291, 1998). 
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995). 
Perlman et al described the vitamin D analog I as a PR ligand (Tetrahedron. Lett. 35, 2295, 1994). 
Hamann et al described the PR antagonist J (Ann. N.Y. Acad Sci. 761, 383, 1995). 
Chen et al described the PR antagonist K (Chen et al, POI-37, 16th Cong. Het. Chem., Montana, 1997). 
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997). 
There are several examples of 2,1-benzisothiazoline 2,2-dioxides (xe2x80x98sultamsxe2x80x99) in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (J. Heterocycl. Chem. 23(6), 1645-9, 1986). 
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. Pat. No. 3,635,964). 
Kamireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 95/33746). 
This invention provides progesterone receptor antagonists of Formula 1 having the structure 
wherein
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain xe2x80x94CH2(CH2)nCH2xe2x80x94, xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94, xe2x80x94O(CH2)pCH2xe2x80x94, O(CH2)qOxe2x80x94, xe2x80x94CH2CH2OCH2CH2xe2x80x94, xe2x80x94CH2CH2NR7CH2CH2xe2x80x94; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n=1-5;
p=1-4;
q=1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted_or, CORA;
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, xe2x80x94CN, xe2x80x94NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure, 
X is halogen, OH, xe2x80x94CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, xe2x80x94NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, xe2x80x94CORB, xe2x80x94OCORB, or xe2x80x94NRCCORB;
RB is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
Rc is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, xe2x80x94CN, xe2x80x94NO2, alkoxy, alkyl, or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2 alkyl, alkoxy, aminoalkyl, CORD, and NRECORD;
RD is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
RE is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Preferred compounds of this invention are those having the structure: 
wherein
R1 and R2 are taken together form a ring and together contain xe2x80x94CH2(CH2)nCH2xe2x80x94;
n=2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a trisubstituted phenyl ring having the structure, 
X is halogen, OH, xe2x80x94CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, xe2x80x94NO2, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, xe2x80x94CN, xe2x80x94NO2, alkoxy, alkyl, or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those having the structure 
wherein
R1 and R2 are taken together form a ring and together contain xe2x80x94CH2(CH2)nCH2xe2x80x94;
n=2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a disubstituted phenyl ring having the structure, 
X is halogen, xe2x80x94CN, or xe2x80x94NO2;
Y is hydrogen, halogen, xe2x80x94CN, xe2x80x94NO2, alkoxy, alkyl, or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NO2;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; xe2x80x9calkenylxe2x80x9d includes both straight- and branched-chain alkyl group of 2-6 carbon atoms containing at least one carbon-carbon double bond; xe2x80x9calkynylxe2x80x9d group includes both straight- and branched-chain alkyl group of 2-6 carbon atoms with at least one carbon-carbon triple bond.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl groups.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl substituted by one or more substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4-14 membered monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized, as an N-oxide, sulfoxide, or sulfone. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, firyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe a heterocyclic having one or more substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl.
The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl.
The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl.
The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl.
The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. This term is also referred to as alkoxycarbonyl.
The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom.
The term xe2x80x9chalogenxe2x80x9d is defined as Cl, Br, F, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropyl-ammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpho-linium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methyl-piperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium, phenylmonoethanolammonium, and the like.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention. 
According to Scheme 1, commercially available sulfonyl chloride 4 is converted via the sulfonamide 5 to the 2,1-benzisothiazoline 2,2-dioxide 6 as described in the literature (Chiarino et al, J Heterocycl. Chem. 23(6), 1645-9, 1986). The nitrogen atom of sultam 6 is then protected by a suitable protecting group, e.g., trimethyl silyl ethyl.
The protected sultam 7 next is treated with a strong organo-metallic base (e.g., butyl lithium, lithium diisopropylamide, potassium hexamethyldisilylazide) in an inert solvent (e.g., THF, diethyl ether) under nitrogen at reduced temperature (caxe2x88x9220xc2x0 C.) (Kende et al, Synth. Commun. 12, 1, 1982). The resulting di-anion then is treated with excess electrophile such as an alkyl halide, preferably the iodide. If R1 and R2 are to be joined such as the product contains a spirocycle at position 3, then the electrophile should be bifunctional, i.e., a diiuodide. Subsequent bromination of the sultam 8 proceeds regioselectively at room temperature with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to give the aryl bromide 9. Judicious choice of reaction conditions may facilitate simultaneous removal of the protecting group at this step.
The bromide 9 then is reacted with a palladium salt (e.g., tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g., THF, dimethoxyethane, ethanol, toluene) under an inert atmosphere (argon, nitrogen). The mixture then is treated with an arylboronic acid or arylboronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions at elevated temperature to give the biphenyl sultam 10. Finally, the protecting group is removed under appropriate conditions and the final product 11 is isolated and purified by standard means.
If R1 and R2 are different then the intermediate is prepared by reacting the dianion of 7 with one equivalent of the electrophile R1xe2x80x94X (X=leaving group, e.g., iodide). The resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using R2xe2x80x94X, or alternatively used in situ for the second alkylation with R2xe2x80x94X. Alternatively, if the desired product is to contain R2=H, then the isolated mono-alkylated intermediate is taken though the subsequent steps. 
Other methodologies also are available for coupling the aryl group, Ar, to the sultam platform: for example, reaction of the bromide 9 with an aryl stannane, aryl zinc, or aryl magnesium halide in the presence of a palladium or nickel catalyst (Scheme 2). The required aryl-metallic species are formed via standard techniques. Furthermore, the bromide 9 may be converted to an aryl boronic acid via standard procedures (treatment with n-butyllithium followed by addition of trimethyl borate and subsequent boronic ester hydrolysis) that will then undergo the range of previously described coupling procedures with a suitable aryl bromide.
The antiprogestational activity of the compounds of this invention was demonstrated in an in vitro standard pharmacological test procedure which evaluated the antiprogestational potency of a representative compound of this invention by measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The procedure used and results obtained are described in Example 2 below.
The results obtained in this standard pharmacological test procedure demonstrate that the compounds of this invention are progestational antagonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ovarian, uterine and endometrial cancers.
The compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens.
The compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier may be solid or liquid.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in liquid or solid composition form.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 xcexcg/kg-750 xcexcg/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated. Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The following provides the preparation of a representative compound of this invention.